tbuckley/cabot-search huggingface dataset:
Abstract 1132: Exploiting MGMT loss using a new class of DNA modifiers which selectively target tumor DNA and overcome therapy resistance mechanisms across multiple tumor types
Authors: Bruce Ruggeri, Kyle Tarantino, Ranjini Sundaram, Kingson Lin, Seth Herzon, Joseph Park, Spenser Johnson, Susan Gueble, Ranjit S. Bindra
Journal: Cancer Research (2023)

Abstract DNA damage response (DDR) defects are common in cancer, and it is well established that these tumor-associated DNA repair vulnerabilities can be exploited for a therapeutic gain. Small molecule inhibitors of DDR proteins have been developed to target these cancers, which are now FDA-approved and/or currently being tested in clinical trials. Our team recently reported on an entirely new approach to exploit DDR defects in cancer, via DNA modification, eliminating the need to target proteins (Lin et al., Science 2022). In this recent study, we demonstrated that our new class of “DNA modifiers (DMs)” can be engineered to exploit loss of O6-methylguanine methyltransferase (MGMT), which leads to robust and selective killing of MGMT-deficient glioma tumors, both in vivo and in vitro. We also found that our approach could overcome acquired and intrinsic defects in another DDR pathway, mismatch repair (MMR), which is a known resistance mechanism to standard-of-care cytotoxic therapies in glioma, including TMZ. Here, we sought to determine the extent to which our approach can be expanded to selectively target a wide range of cancers beyond glioma in which loss of MGMT, as well as acquired and intrinsic MMR defect, are commonly seen at various frequencies. To this end, we profiled over 900 cell line models, as well as several collections of patient-derived cultures derived from several tumor types for sensitivity to our DMs based on MGMT and MMR status in vitro. We then validated our findings in cell line xenograft and patient-derived xenograft models, in vivo. In parallel, we compared the activity of DMs to commonly used, standard-of-care cytotoxic drugs, in vitro and in vivo. Our data indicate that DMs can effectively target MGMT loss, as well as intrinsic and acquired MMR defects, in multiple non-CNS tumor types. Taken together, the findings reported here support an entirely new approach to selectively exploit DDR defects via direct DNA modification. This new approach has the potential to overcome known resistance mechanisms to currently used small molecule inhibitors of DDR proteins, across a broad range of cancers. Citation Format: Bruce Ruggeri, Kyle Tarantino, Ranjini Sundaram, Kingson Lin, Seth Herzon, Joseph Park, Spenser Johnson, Susan Gueble, Ranjit S. Bindra. Exploiting MGMT loss using a new class of DNA modifiers which selectively target tumor DNA and overcome therapy resistance mechanisms across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1132.
Abstract 5697: Predicting response to PD-L1 inhibition in NSCLC using a quantitative systems pharmacology model guided by immunogenomic data
Authors: Hanwen Wang, Theinmozhi Arulraj, Aleksander S. Popel
Journal: Cancer Research (2023)

Abstract Introduction: Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with an overall 5-year survival rate of 26%, which varies by the disease stage. Novel drug combinations involving immune checkpoint inhibitors are being investigated in clinical trials in NSCLC. In this study, we generated about 450 virtual patients that resembled actual patients with NSCLC and simulated tumor growth during PD-L1 inhibition using a quantitative systems pharmacology (QSP) model. Methods: We recalibrated a previously developed QSP model of the cancer-immunity cycle (1) to NSCLC with parameters estimated by published experimental data. Proportions of CD8, CD4, and regulatory T cells (Tregs), M1 and M2 macrophages in lung adenocarcinoma and lung squamous cell carcinoma were downloaded from iAtlas database and used to calculate the ratios of CD8/CD4, Tregs/CD8, and M1/M2. The three immune subset ratios (observed data) were used to guide the virtual patient generation. We first randomly generated deviations around the baseline model parameters to account for inter-patient variability and then selected virtual patients with model-predicted immune subset ratios statistically matching the observed data. Finally, we simulated tumor growth during PD-L1 inhibition and predicted clinical response in the virtual patient cohort. Results: Our model predicted an overall response rate of 16.3% with a 95% bootstrap confidence interval of (11.8, 22.4)% for the overall virtual patient cohort. It also showed that CD8 T cells, PD-L1 expression, CD8/CD4, CD8/Tregs, M1/M2 ratios, and the number of NSCLC-specific T cell clones were significantly higher in responders to PD-L1 inhibition. Furthermore, Tregs/CD8 and CD8/CD4 ratios were predicted to be the best predictive biomarkers according to ROC analysis with areas under ROC curve of 0.71 and 0.66. Conclusion: Immunogenomic analysis of RNA-seq data on iAtlas allowed generation of realistic virtual patients using QSP models in immuno-oncology. With a virtual patient cohort guided by immunogenomic data, our model provided reliable efficacy prediction for immunotherapy and a tool to identify predictive biomarkers in NSCLC. 1. Wang H, Zhao C, Santa-Maria CA, Emens LA, Popel AS. Dynamics of tumor-associated macrophages in a quantitative systems pharmacology model of immunotherapy in triple-negative breast cancer. iScience. 2022;25:104702. Citation Format: Hanwen Wang, Theinmozhi Arulraj, Aleksander S. Popel. Predicting response to PD-L1 inhibition in NSCLC using a quantitative systems pharmacology model guided by immunogenomic data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5697.
Abstract 2046: Identification of the cuproptosis-related gene signature associated with the tumor environment and prognosis of patients with glioblastoma multiforme (GBM)
Authors: Yaman B. Ahmed, Ayah N. Al-Bzour, Ghayda'a N. Al-Majali, Zaid M. Khalefa, Saja M. Alzghoul
Journal: Cancer Research (2023)

Abstract Background: Glioblastoma multiforme (GBM) is the most common tumor of the central nervous system with poor prognosis. Cuproptosis is a novel programmed cell death pathway targeting lipoylated tricarboxylic acid cycle proteins. Previous studies have found that it participates in tumor progression, but its role in GBM is still elusive. In this study, we aimed to develop a cuproptosis gene-signature risk score using bioinformatics analysis and machine learning. Methods: We acquired transcriptomic and clinical information of GBM patients from The Cancer Genome Atlas (TCGA). A total of 2283 differentially expressed genes (DEGs) were obtained from the GEPIA2 database. 26 cuproptosis-related genes (CRGs) were retrieved from literature. A correlation analysis between the 26 CRGs and the DEGs were conducted to retrieve the cuproptosis-related DEGs. Then, a univariate cox analysis was conducted to obtain the prognostic-related DEGs for overall survival (OS). The least absolute shrinkage and selection operator (LASSO) were conducted for regularization and the gene risk score was constructed using the multivariate cox coefficients. Results: A total of 731 downregulated DEGs were correlated with CRGs, while 68 upregulated DEGs were correlated with CRGs and were further screened for prognostic value using the univariate cox analysis. A total of 70 prognostic related CRGs were identified and were further screened using the LASSO cox analysis. After multivariate cox analysis, a total of seven genes were significantly associated with survival (p-value&amp;lt;0.01). A risk-score gene signature was constructed from the cox coefficients multiplied by the expression of the following genes: -0.0012*DPP10+0.0021*EGR4+0.0015*ITPKA+ 0.0003* PTPRN+ 0.0007* STEAP2+ 0.0006* TENM2+- 0.0017* ZNF540. Conclusion: Univariate and multivariate Cox regression analyses showed the CRGs-based prognostic signature independently functioned as a risk factor for OS in GBM patients. Furthermore, our results gave a promising understanding of cuproptosis in GBM, as well as a tailored prediction tool for prognosis and immunotherapeutic responses in patients. Citation Format: Yaman B. Ahmed, Ayah N. Al-Bzour, Ghayda'a N. Al-Majali, Zaid M. Khalefa, Saja M. Alzghoul. Identification of the cuproptosis-related gene signature associated with the tumor environment and prognosis of patients with glioblastoma multiforme (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2046.
Abstract 1881: Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-306 targeting IL-13Rα2 in immuno-oncology
Authors: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Yuan Li, Xia Qin, Da Fei, Runsheng Li
Journal: Cancer Research (2023)

Abstract Interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed in various types of cancers including glioma and melanoma and is known to be associated with increased tumor invasiveness and metastases. Here, we present the preclinical efficacy and toxicity results for a novel, anti-IL-13Rα2 ADC-LM-306. In vitro binding activity and internalization of LM-306 and LM-106 (unconjugated antibody of LM-306) were assessed in human IL-13Rα2 overexpressing and endogenous cell lines using flow cytometry. The antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cytotoxicity were assessed using viability assays. Cross-species reactivity of drug was assessed in cells expressing cynomolgus, rat and mouse IL-13Rα2. In vivo A375 CDX model was used to assess the effect of LM-306 anti-tumor activity. The toxicity of LM-306 was evaluated in repeated-dose intravenous dose range-finding (DRF) toxicity and single intravenous maximum tolerated dose (MTD) study in cynomolgus monkeys. Both LM-106 and LM-306 showed concentration dependent binding affinity to IL-13Rα2 in various cell lines (Table 1). In addition, LM-106 also showed a dose dependent internalization and ADCC and LM-306 showed significant cytotoxicity in all cell lines (Table 1). Furthermore, LM-306 showed comparable binding affinity to human IL-13Rα2 to its unconjugated counterpart LM-106 (KD:7.43E-10 vs 1.77E-9). LM-306 was also found to be cross-reactive toward cynomolgus IL-13Rα2. In vivo, LM-306 showed tumor growth inhibition at a dose of 1, 3, 10 mg/kg given intravenously once weekly, indicating its strong anti-tumor activity. The highest non-severely toxic dose of LM-306 was determined to be 9 mg/kg in the DRF study and MTD was determined to be 18mg/kg in MTD study for male monkey. In summary, LM-306 showed high binding affinity to human IL13Rα2 expressing cells with potent cytotoxicity in vitro and significant in vivo inhibition of tumor growth, suggesting its therapeutic benefit in immuno-oncology. Summary of parameters of LM-106 and LM-306 binding affinity, internalization, ADCC and cytotoxicity Assay Antibody EC50 (nM) HEK293/H_IL-13Rα2 U251 A375 SKMEL5 Binding affinity LM-106 0.99 0.21 0.57 0.1 LM-306 1.47 0.33 0.8 0.12 Internalization LM-106 2.22 - 0.43 - ADCC LM-106 0.16 - 0.03 - LM-306 0.31 - 0.03 - Cytotoxicity (IC50) LM-306 0.03 0.05 0.01 0.005 Citation Format: Wentao Huang, Zhifang Liu, Yifan Li, Heng Pan, Yuan Li, Xia Qin, Da Fei, Runsheng Li. Pre-clinical evaluation of a novel antibody drug conjugate (ADC) LM-306 targeting IL-13Rα2 in immuno-oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1881.
Abstract 4518: Highlighting the prenatal, natal, and early childhood risk factors of cancer: seeking better opportunities for cancer prevention
Authors: Abeer Abd Elmoneim, Ayat Roushdy, Ehab Metwally
Journal: Cancer Research (2023)

Abstract Background: Fostering new public health approaches to cancer prevention is required to reduce the number of new cases. Early life exposures, to carcinogens may affect different phases of the multi-tage clonal expansion model of carcinogenesis. Critical development periods, in-utero and puberty, exposures may induce permanent changes in tissue differentiation, metabolism, and gene expression that influence cancer risk. Epigenetic modifications are also critical for regulating cellular processes and responses during development that are maintained overtime. Therefore, promising strategies should develop for cancer prevention mainly on environmental approaches. We aim in this study to assess the prevalence of risk factors of childhood cancer in Almadinah City, a local community in Saudi Arabia, and to address cancer prevention opportunities during prenatal, natal and early children life. Patients and Methods: The study is a cross section observational study. The population includes convenient samples of pregnant mothers, neonates and preschool children. Data regarding natal, prenatal and early childhood risk factors of cancer collected using a predesigned questionnaire. Results: Early life exposure to cancer risks increases prevalence of cancer. Risk factors like high birth weight, maternal obesity and smoking are the most frequent risks followed by chromosomal anomalies and genetic syndromes. Prenatal use of folic acid, breastfeeding and allergy, respectively, are the most frequent protective factors against cancer development. conclusions: Strict approaches should be designed for preventing early life exposures and their cumulative effect that can lead to cancer development. Citation Format: Abeer Abd Elmoneim, Ayat Roushdy, Ehab Metwally. Highlighting the prenatal, natal, and early childhood risk factors of cancer: seeking better opportunities for cancer prevention. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4518.
Abstract 4286: A statistical learning method for simultaneous copy number estimation and subclone clustering with single cell sequencing data
Authors: Feifei Xiao, Fei Qin, Guoshuai Cai
Journal: Cancer Research (2023)

Abstract The availability of single cell sequencing (SCS) enables us to assess intra-tumor heterogeneity and identify cellular subclones without the confounding effect from mixed cells. Copy number aberrations (CNAs) have been commonly used to identify subclones in SCS data since cells comprising a subpopulation are found to share genetic profile. However, currently available methods may generate spurious results (e.g., falsely identified CNAs) in the procedure of CNA detection, hence diminishing the accuracy of subclones identification from a large complex cell population. In this study, we developed a CNA detection method based on a fused lasso model, referred to as FLCNA, which can simultaneously identify subclones in single cell DNA sequencing (scDNA-seq) data. Spike-in simulations were conducted to evaluate the clustering and CNA detection performance of FLCNA benchmarking to existing copy number estimation methods (SCOPE, HMMcopy) in combination with commonly used clustering methods. FLCNA was also applied to a real scDNA-seq dataset with breast cancer and clusters identified using FLCNA showed clearly different genomic variation patterns. In conclusion, FLCNA provided superior performance in subclone identification and CNA detection with scDNA-seq data. Citation Format: Feifei Xiao, Fei Qin, Guoshuai Cai. A statistical learning method for simultaneous copy number estimation and subclone clustering with single cell sequencing data. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4286.
Abstract 1800: An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade
Authors: Seung Joon Lee, Won Suk Lee, Eun-Jin Go, Hannah Yang, Hong Ro Kim, Bong-Seog Kim, Chan Kim, Hong Jae Chon
Journal: Cancer Research (2023)

Abstract Background: PI3Kδ and PI3Kγ are mainly expressed in leukocytes, indicating that they are involved in immune modulation of the tumor microenvironment (TME). Additionally, DNA-dependent protein kinase (DNA-PK) plays a pivotal role as a mediator in repairing DNA damage in cancer cells. Here, we developed a triple inhibitor of PI3Kδ/γ and DNA-PK, BR101801, to promote antitumor immune responses and thereby enhance therapeutic efficacy of the PD-1 immune checkpoint inhibitor. Methods: CT26 and MC38 colon tumor-bearing immunocompetent mice were treated with BR101801 (50 mg/kg, PO) daily and/or anti-PD-1 (8 mg/kg, IP) twice a week. The tumors were comprehensively analyzed using flow cytometry, multiplex tissue imaging, and NanoString profiling methods. Results: Oral administration of BR101801 suppressed tumor growth without significant toxicities. The optimal schedule for BR101801 was determined by activation of T cell immunity in the TME. BR101801 monotherapy significantly increased CD8+ cytotoxic T cells and decreased CD4+CD25+Foxp3+ regulatory T cells, while no changes were observed in tumor-associated macrophages. Moreover, BR101801 increased AH-1+ tumor-specific CD8+ T cells within BR101801-treated CT26 tumors. BR101801 induced extensive immune remodeling of the TME by altering immune-related genes. Notably, gene signatures related to DNA damage and inflammatory responses were more enriched in BR101801-treated tumors. Furthermore, the combination immunotherapy of BR101801 and anti-PD-1 antibody strongly suppressed tumor growth and improved antitumor immunity within the TME, leading to complete tumor regression. Conclusion: Our study demonstrates that BR101801, an oral triple inhibitor of PI3Kδ/γ and DNA-PK, effectively elicited anticancer immune responses within the TME and potently inhibited tumor progression in combination with immune checkpoint blockade. Citation Format: Seung Joon Lee, Won Suk Lee, Eun-Jin Go, Hannah Yang, Hong Ro Kim, Bong-Seog Kim, Chan Kim, Hong Jae Chon. An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1800.
Abstract 1312: Oncogenic mutant p53 proteins are selectively shuttled by cancer extracellular vesicles toeducate the tumor microenvironment
Authors: Bibek Bhatta, Ishai Luz, Christian Krueger, Fanny Xueting Teo, David P. Lane, Kanaga Sabapathy, Tomer Cooks
Journal: Cancer Research (2023)

Abstract IntroductionMost cancers harbor mutations in the TP53 gene (encoding for the p53 tumor suppressor protein). Furthermore, gain-of-function (GOF) mutation in p53 imparts an aggressive traits to the cells when compared to the cancer cells harboring inactivating mutations or wild-type (WT)-p53. Notably, multiple studies have delineated the presence of GOF-mutant p53 protein in untransformed cells or in stromal compartments of tumor microenvironment (TME). In recent years, the involvement of extracellular vesicles (EVs) in cell-to-cell communication has emerged as a major route by which cancer cells can interact and educate immune, and non-immune cells in TME to become tumor supportive. To this end, we hypothesize that mutant p53 protein can be shuttled via EVs to TME cells thus shedding light on a novel non-cell autonomous role of mutant p53 cancers.MethodsEVs were isolated from various cancer cell lines (pancreas, lung, colon) differing by their p53 status and the effect on neighboring cancer cells and TME cells was studied in vitro and in-vivo. We also utilized the human colorectal Colo-320DM cancer cell xenograft model, which expresses the R248W p53 mutant. FFPE sections of subcutaneous tumors derived from the Colo-320DM xenografts were stained for p53 using the DO-1 antibody that specifically recognizes human p53.ResultsOur data demonstrated that mutant p53 protein can be selectively sorted into EVs; that mutant p53 in EVs can be taken up by neighboring cancer cells and macrophages that do not harbor mutant p53 protein. Evident of macrophage education was seen with the increased expression and secretion of pro-inflammatory cytokines. Notably, mutant p53 expression was also found in non-tumor cells in both human cancers, and in non-human tissues in human xenografts.SummaryCancer cells harboring GOF p53 mutants, can package mutant p53 proteins in EVs, and deliver them to neighboring cancer cells and to the TME. Citation Format: Bibek Bhatta, Ishai Luz, Christian Krueger, Fanny Xueting Teo, David P. Lane, Kanaga Sabapathy, Tomer Cooks. Oncogenic mutant p53 proteins are selectively shuttled by cancer extracellular vesicles toeducate the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1312.
Abstract 2052: High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered
Authors: Sudarshawn Damodharan, Alyssa Rosenbloom, Mahua Dey
Journal: Cancer Research (2023)

Abstract Background: Diffuse midline glioma (DMG), H3 K27-altered are highly aggressive malignancies of the central nervous system that affect both pediatric and adult populations. The immune layout and genetic changes within the tumor microenvironment associated with these high-grade malignancies are thought to play an integral role in the phenotypic differences in tumor presentation and clinical course between both populations. Comparative landscapes between pediatric and adult DMGs is not known. Methods: The NanoString GeoMxTM Digital Spatial Profiler platform was used to determine the immune marker and genetic layout in a cohort of both pediatric and adult DMG, H3 K27-altered tissue samples. Three fluorescently labeled antibodies targeting immune cells (CD45), epithelial cells (PanCK), tumor cells (H3 K27M) and a nucleic acid stain (SYTO-13) were used to identify and separate out the various components within the tumor tissues from selected regions of interest. The resultant information was then pooled into libraries that were run through the Illumina sequencing platform to assess transcriptomic and proteomic data for both cohorts of samples. Results: Our data revealed the immune and genetic expression seen within both populations across multiple regions of interest within the samples. Differences were seen specific to each population that may have clinical significance and warrant further exploration including a significant increase in genes associated with RTK pathways in the pediatric samples. Conclusion: The digital spatial analysis of pediatric and adult DMG, H3 K27-altered shows differences within the molecular landscape which may contribute to the clinical differences between both populations. These observed differences may play a role in future treatments and further research is needed to explore this. Citation Format: Sudarshawn Damodharan, Alyssa Rosenbloom, Mahua Dey. High-plex spatial multiomics of pediatric and adult diffuse midline glioma, H3 K27-altered [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2052.